To Report or Not to Report?

It was a problem similar to one previously handled by the IACUC of Great Eastern University. Heather Jones, Chairwoman of the Department of Biochemistry, meekly told Pete Wagner, Chairman of the University’s IACUC, that one of her faculty had inadvertently used some rats in research that was not IACUC-approved. As Jones explained it, Harry Weiss, a coinvestigator on Laura Kasik’s IACUC protocol, thought that Kasik had amended her protocol to include an additional experimental group for Weiss. Unfortunately, that never happened because Kasik thought Weiss himself had requested the amendment. All in all, she said, it was just an oversight. IACUC Chairman Wagner was not happy that the faculty would simply take for granted the IACUC’s approval of an amendment request, but, he rationalized, at least he didn’t have to do much of an investigation. Everybody knew exactly what had happened, and everybody readily admitted it.

Wagner presented the entire scenario to the IACUC. Weiss had taken five young adult obese rats that had not yet been entered into Kasik’s cardiovascular study, and, using Kasik’s IACUC protocol, fed them their standard high-cholesterol diet. He then began to take 0.2 ml blood samples once a week, by briefly restraining the animal and using a scalpel blade to make a small nick in the tail vein. This continued for four weeks, giving Weiss the data he needed. At that time, he casually mentioned his results to Jones. Knowing that Weiss tended to be forgetful, Jones asked him about IACUC approval, thus starting the cascade of events that led to the current meeting of the IACUC.

Everybody on the IACUC thanked Jones for coming forward with the information. There was no doubt that there had been a protocol violation, but there was no way to suspend Weiss’ small study, as it had already been completed. The real question, said Wagner, was whether the violation was sufficiently serious to merit any action at all against Kasik or Weiss. Both of the researchers were cooperative, although they did think that this was much ado about nothing. Neither of them had had previous problems with the IACUC. Wagner reminded the IACUC that if there was a vote to suspend any of the previously approved and ongoing activities of the protocol in question, or any other of the investigators’ protocols, he would have to notify the appropriate federal funding agency and the Office of Laboratory Animal Welfare (OLAW). On the other hand, said Wagner, even if there was no vote for suspension, he still would have to notify OLAW of the incident if the IACUC determined that this was a serious noncompliance with the Public Health Service (PHS) Policy. Some members asked if the IACUC could just vote to send a warning letter or a letter of reprimand. “Of course,” said Wagner, “whether or not any action at all is necessary is entirely up to the IACUC.”

Did Wagner provide correct information to the IACUC? Do you think that this incident was important enough to report to the federal government?

Much Ado About Nothing?

Richard E. Doyle, DVM

This reviewer tends to agree with the investigators’ position; to make a bigger issue out of this incident than has already been done could very well amount to “overkill.” Weiss used five rats assigned to a project on which he is a coinvestigator, and used them as “an additional experimental group.” The degree to which the “group” was variant is not clear. From the narrative, we can assume that the bleeding regimen was different. Furthermore, Kasik was aware that the variant use was sufficiently different to require an amendment, which she thought Weiss had received. Given the information presented, it is likely that the IACUC would have approved an amendment, had it been requested. It is also relevant that none of the principals had a history of compliance problems.

From all indications, Wagner has gathered the appropriate information and presented it to the Committee, along with an accurate assessment of their range of possible actions. My conclusion is that what occurred is neither much ado about nothing nor serious noncompliance. Furthermore, there appears to be no serious deviation from the provisions in the Guide. Therefore, no one should be suspended and no report need be filed with OLAW. The incident should be documented in writing, and reviewed and approved by the IACUC. The written documentation should include the importance of timely submission and approval of amendments, and copies provided to all parties.

Section IV.F.3 of PHS Policy requires an IACUC to report promptly to OLAW any (1) serious or continuing noncompliance with the PHS Policy, (2) serious deviation from the provisions of the Guide, or (3) suspension of an activity by the IACUC. Therefore, the IACUC Chair is incorrect in his statement that “whether or not any action at all is necessary is entirely up to the IACUC.” Although the IACUC is allowed some degree of flexibility in determining which incidents fall under category 1 or 2, PHS Policy IV.B.7 stipulates that the IACUC must “review and approve, require modifications in (to secure approval), or withhold approval of proposed significant changes regarding the use of animals in ongoing activities.”

The incident described here involves the addition of animals and change in experimental procedures (that is, an “additional experimental group,” implying that all or some of the procedures are not described in the approved protocol). Because these modifications were implemented without prior IACUC approval, the IACUC did not have the opportunity to conduct an appropriate review as required by the PHS Policy and the Guide; moreover, topics such as the rationale and purpose of the new experimental group, justification for the number of animals, method of euthanasia or disposition of animals, and appropriateness of the blood collection method were not considered. Therefore, the incident falls under both categories 1 and 2 above and should be reported to OLAW.

Kasik and Weiss were aware that an additional experimental group would require an amendment to their existing protocol, and the IACUC agreed that the investigators’ failure to obtain approval for this new experimental group constituted a protocol violation. PHS Policy IV.C.6 states that the IACUC “may suspend an activity that it previously approved if it determines that the activity is not being conducted in accordance with applicable provisions of the Animal Welfare Act, the Guide, the institution’s Assurance, or IV.C.1” of the PHS Policy. Therefore, that the additional experiments had already been completed does not preclude the IACUC suspending the investigators’ existing protocol until the investigators provide formal assurance to the IACUC that this type of “oversight” will not recur. This assurance may be particularly warranted given the statement that the investigators thought “this was much ado about nothing.” However, regardless of the IACUC’s decision (that is, suspend the protocol or simply “send a warning letter or a letter of reprimand”), the IACUC should use this opportunity to educate the investigators regarding review requirements, and should file a report with OLAW describing the incident as well as the resolutions.

Crispino is Assistant Director–Education, Chancellor’s Animal Research Committee, and Gerow is Associate Director–Animal Subjects Research, Office for Protection of Research Subjects, University of California, Los Angeles, CA.

It’s All in the Interpretation

Margaret Batchelder, DVM, Dip. ACLAM, and Erik Dohm, DVM

Wagner’s report to the IACUC was essentially correct. According to PHS Policy, OLAW must be notified by the IACUC, through the Institutional Official, regarding “… any serious or continuing noncompliance with this Policy; any serious deviation from the provisions of the Guide; or any suspension of an activity by the IACUC.” Although corrective actions, other than full protocol suspension, are in fact the responsibility of the Institutional Official (IO), in most cases the IO will comply with the recommendations reached by the IACUC after its discussion of the issue.

It is clear that noncompliance with PHS Policy, however inadvertent, has occurred in this case. However, in the absence of a definition of “serious,” the IACUC and IO are left to assess the severity of the violation, with the reporting requirements dependent on this assessment. If they decide the noncompliance is “serious,” or the IACUC votes to suspend the protocol, then they must report the incident regardless of any other action taken. Should they judge the incident less serious, the Committee and IO can handle it as they consider appropriate, recording their decisions in the IACUC minutes, with no formal reporting requirement.

Because of the sensitive nature of investigating noncompliance, it is recommended that the IACUC have an institutional policy to guide them in the process of investigation and in determining the severity of an incident. It is reasonable to assume that noncompliant activities that endanger the health or welfare of animals or people should be accorded a higher level of concern. There may also be circumstances (such as repeated or apparently deliberate violations) that increase the level of concern for even a minor infringement. Nevertheless, no policy can predict every possible circumstance, so each case will still need to be addressed on an individual basis. The Committee Members should keep in mind that precedents are established with each decision and should strive to keep their decisions fair and consistent.

Having decided on the “seriousness” of the noncompliance, the IACUC must then discuss what action, if any, should be recommended to the IO. Actions may be corrective or punitive, proactive or retroactive. In this case, because the noncompliant activity has already occurred, suspension of the main protocol would probably be considered excessively punitive. It might be more appropriate to deal with the problem in a letter to the investigator, stressing the importance of ensuring that such an oversight does not recur, and outlining what actions the Committee might take if there is a recurrence. In addition, the Committee could require that the protocol amendment be submitted and approved retroactively. The investigator might also be required to attend a training session in regulatory/protocol issues.

Such responses are similar to those taken by our own IACUC in previous cases of noncompliance that were “not serious.” We realize that cooperative and corrective rather than retaliatory actions are most likely to bring about the desired results. By taking a firm but noncombative approach, our IACUC hopes to foster the investigators’ confidence in the Committee’s authority, while reinforcing the importance of regulatory compliance.

Batchelder is the Assistant Director for Animal Health and Dohm is a Clinical Veterinarian for the Institute for Animal Studies at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY.

A Word From OLAW

In response to the questions posed in this scenario, the Office of Laboratory Animal Welfare (OLAW) offers the following clarification and guidance:
As with most hypothetical IACUC scenarios, this one requires that a few assumptions be made before analyzing it systematically. This commentary will assume PHS Policy applicability either by virtue of PHS support for Kasik’s animal-related project, or as a result of the Institution’s commitment in its Assurance to apply a uniform standard to all animal activities. It also assumes that the IACUC already has policies in place to determine whether the changes Weiss made to the ongoing protocol are, by its own definition, significant changes requiring review.

Although the IACUC does have some discretion in defining what changes are considered significant, it appears obvious from the subsequent universal recognition of error that an amendment is required in this case. This interpretation is also consistent with the 15-year history of PHS Policy guidance and examples from OLAW on the subject of the significance of protocol changes1,2. Because PHS Policy requires IACUC review and approval of all significant protocol changes, failure to do so is clearly noncompliant with the PHS Policy.

Other reviewers have correctly identified the three circumstances that trigger mandatory prompt reporting to OLAW. There does not appear to be a suspension in this case. Although the other two reporting circumstances require IACUC judgments on the degree of seriousness associated with noncompliance with the Policy or deviation from the provisions of the Guide, these judgments are not the exclusive prerogative of the IACUC. Again, OLAW has provided guidance and examples of where it believes that threshold lies1,3–5. OLAW has already indicated its determination that the conduct of unapproved animal research activity is clearly serious and reportable. Regardless of the issues of investigator intent, history, or subsequent harm to animals, circumvention of institutional animal welfare oversight mechanisms for prospective IACUC review constitutes serious noncompliance with the PHS Policy.

Great Eastern should not hesitate to report this incident. If in doubt, a preliminary phone call to OLAW can help clarify expectations and alleviate apprehensions. OLAW views such reporting as evidence that the system is working. Conversely, nonreporting may result in loss of confidence in the institutional animal program. The institution retains a great deal of latitude in how it resolves specific problems and prevents their recurrence. OLAW bases its acceptance of institutional corrections of noncompliance on the effectiveness of those corrections and preventive measures. Adverse actions against institutions are normally not considered when institutions themselves identify, report, and correct noncompliance. On the other hand, failure to report incidences of noncompliance promptly may convert an investigator transgression into an even more serious form of institutional noncompliance, one that could jeopardize the status of the institution’s Assurance and eligibility for funding.

We should also consider NIH grants policy in this scenario. Although certain changes in funded scientific research programs are allowable, some require prior notification of NIH grants management or program staff. Also, compliance with the PHS Policy, including prior IACUC approval of significant changes, is a term and condition of award. Failure to satisfy these commitments exposes the institution to potential disallowance of charges against the grant and other more serious sanctions.

Publication of articles in many refereed journals requires conformity with certain editorial or professional society animal welfare policies. Most are clear about accepting only those studies conducted under fully compliant conditions. Therefore, the integrity of the investigator and the institution could be damaged by misrepresentation of the conditions under which Weiss’ animal work was conducted.

The take-home message is that IACUCs have tremendous latitude and discretionary authority under the PHS Policy. Nevertheless, it is important to exercise that authority within established PHS Policy and NIH grants policy limits.